The role of proteolytic processing in the morphogenesis of virus particles.

Proteinases are encoded by many RNA viruses, all retroviruses and several DNA viruses. They play essential roles at various stages in viral replication, including the coordinated assembly and maturation of virions. Most of these enzymes belong to one of three (Ser, Cys or Asp) of the four major classes of proteinases, and have highly substrate-selective and cleavage specific activities. They can be thought of as playing one of two general roles in viral morphogenesis. Structural proteins are encoded by retroviruses and many RNA viruses as part of large polyproteins. Their proteolytic release is a prerequisite to particle assembly; consequent structural rearrangement of the capsid domains serves to regulate and direct association and assembly of capsid subunits. The second general role of proteolysis is in assembly-dependent maturation of virus particles, which is accompanied by the acquisition of infectivity.     

The role of kinesin, dynein and microtubules in pancreatic secretion

The regulated secretion of pancreatic zymogens depends on a functional cytoskeleton and intracellular vesicle transport. To study the dynamics of tubulin and its motor proteins dynein and kinesin during secretion in pancreatic acinar cells, we infused rats with 0.1 μg/kg/h caerulein. Electron and fluorescence microscopy detected neither dynein nor kinesin at the apical secretory pole, nor on the surface of mature zymogen granules. After 30 min of secretagogue stimulation, kinesin and the Golgi marker protein 58 K were reallocated towards the apical plasma membrane and association of kinesin with tubulin was enhanced. Disruption of acinar cell microtubules had no effect on initial caerulein-induced amylase release but completely blocked secretion during a second stimulus. Our results suggest that mature zymogen granule exocytosis is independent of intact microtubules, kinesin and dynein. However, microtubule-dependent mechanisms seem to be important for the replenishment of secretory vesicles by redistribution of Golgi elements towards the apical cell pole. J. Schnekenburger and I.-A. Weber have contributed equally to this work.     

The potential role of endogenous bacteriophages in controlling invading pathogens

Bacteriophages (phages) are omnipresent in our environment, and recent studies highlight their potential impact on the microbial world. Phages can also be present in mammalian organisms, including man (intestines, oral cavity, urine, sputum and serum). Data are available which suggest that those endogenous phages could play an important role in eliminating bacteria and regulating the body ecosystem. Furthermore, our most recent findings suggest that phages can exert immunosuppressive action in the gut, helping control local inflammatory and autoimmune reactions, and demonstrate anticancer activity. We hypothesize that phages could act in concert with the immune system in immunosurveillance against bacteria, viruses and cancer.article dedicated to Professor Ludwik Hirszfeld to commemorate the 50^th anniversary of his deathReceived 8 September 2004; received after revision 18 October 2004; accepted 21 October 2004     

A role for the hinge/ear domain of the β chains in the incorporation of AP complexes into clathrin-coated pits and coated vesicles

The clathrin-associated adaptor protein (AP) complexes drive the polymerization of clathrin in coated pits to form coated vesicles. It has previously been shown that the carboxyl-terminal hinge/ear domain of the β2 chain contains a binding site for clathrin and that removal of this domain from APs or from isolated β2 chains abrogates their ability to form clathrin coats in vitro. We show here that the hinge/ear domain is necessary for efficient incorporation of AP complexes into coated pits and coated vesicles in cells, a result that is consistent with the view that the β chains indeed provide an important interaction between the AP complexes and clathrin. Received 7 April 1997; received after revision 22 May 1997; accepted 28 May 1997     

Protective and immunostimulating activity of a low dose of cyclophosphamide in the experimental infection of mice with foot-and-mouth disease virus

Summary Administration to mice of a low, non-immunosuppressive dose of cyclophosphamide 4 days before infection with foot-and-mouth disease virus decreases viral replication, enhances the immune response against the virus and prevents panceatic damage.     

In vitro biosynthesis of juvenile hormone III by the corpora allata ofCalliphora vomitoria and its role in ovarian maturation and sexual receptivity

Summary JH III is the only JH detected by GLC-MS in medium from in vitro incubations of corpora allata of adult females ofCalliphora vomitoria. When corpora allata were removed from females at various times during the reproductive cycle and the JH III produced by the glands in vitro measured by a JH III radioimmunoassay, an increase in the level of synthesis was found to occur before previtellogenesis (0–24 h). A second increase appeared at the onset of vitellogenesis (72–83 h) and continued until the end of vitellogenesis (96 h) and the occurrence of chorionation (120 h). Since sexual receptivity develops with vitellogenesis, the significantly higher levels of JH III biosynthesis in vitro at this time supports a possible role for JH in the acquisitive of receptivity.     

CD11b-bearing mononuclear leucocytes and IgA levels in the staging of human immunodeficiency virus infection

Certain immunological parameters (i.e. low CD4+ T cell numbers, high serum soluble CD8) have been described as prognostic factors for the progression of human immunodeficiency virus (HIV) infection to later clinical stages. In the present study we have found in one hundred HIV-infected Spanish patients (81% drug abusers, 7% homosexuals, 6% heterosexuals, and 6% other or unknown risk groups) that CD11b+ peripheral blood mononuclear cells are increased in those with persistent lymphadenopathy as compared to other clinical stages (asymptomatic, AIDS-related complex and AIDS). Serum IgA was significantly increased in AIDS patients, and in patients at any other clinical stage who had concomitant infections (mainly mycobacterial and fungal). CD11b (an integrin with complement receptor functions) may thus be of clinical interest for the staging of HIV-infected patients, and reflect stage-selective immunological changes in mononuclear cell biology during HIV infection. High IgA on the other hand, would be a marker of concomitant infection as well as of disease progression. The results concern mostly drug addicts (the main risk group in Spain), but may apply to the other risk groups because no significant differences were detected between drug addicts (n=81) and non-drug addicts (n=19) for the studied variables (p>0.05).     

The role of the Matthew effect in science

Robert Merton observed that better known scientists tend to get more credit than less well known scientists for the same achievements; he called this the Matthew effect. Scientists themselves, even those eminent researchers who enjoy its benefits, regard the effect as a pathology: it results, they believe, in a misallocation of credit. If so, why do scientists continue to bestow credit in the manner described by the effect? This paper advocates an explanation of the effect on which it turns out to allocate credit fairly after all, while at the same time making sense of scientists’ opinions to the contrary.     

The role of the nuclear envelope in cellular organization

Over the last years it has become evident that the nuclear envelope (NE) is more than a passive membrane barrier that separates the nucleus from the cytoplasm. The NE not only controls the trafficking of macromolecules between the nucleoplasm and the cytosol, but also provides anchoring sites for chromosomes and cytoskeleton to the nuclear periphery. Targeting of chromatin to the NE might actually be part of gene expression regulation in eukaryotes. Mutations in certain NE proteins are associated with a diversity of human diseases, including muscular dystrophy, neuropathy, lipodistrophy, torsion dystonia and the premature aging condition progeria. Despite the importance of the NE for cell division and differentiation, relatively little is known about its biogenesis and its role in human diseases. It is our goal to provide a comprehensive view of the NE and to discuss possible implications of NE-associated changes for gene expression, chromatin organization and signal transduction. Received 8 August 2005; received after revision 13 October 2005; accepted 13 October 2005     

The antiviral effect of Keishi-ni-eppi-ichi-to,a tranditional Chinese herbal medicine,on influenza A2(H2N2) virus infection in mice

The antiviral effect of Keishi-ni-eppi-ichi-to (TJS-064), a traditional Chinese herbal medicine, was investigation in mice infected with influenza A₂(H₂N₂) virus. When mice exposed to 5 LD₅₀ dose of the virus were treated orally with a 70 mg/kg dose of TJS-064 1 day before and 1 day and 4 days after the infection, 100% survived over a 25-day experimental period. At the end of this period all the control mice, treated with saline alone, had died; their mean survival time in days (MSD) was 11.2 days. When mice infected with a 10 LD₅₀ dose of the virus were treated with TJS-064, the MSD was >17.4 days and there was a 50% survival rate, while the control group had a MSD of 8.7 days and 0% survival rate. No significant antiviral effect TJS-064 was observed when the agent was administered orally to mice infected with a 100 LD₅₀ or large dose of influenza virus. Pulmonary consolidation, virus titers in lung tissues and HAI titers in sera of infected mice treated with TJS-064 were all significantly lower than those of infected mice treated with saline. Interferon activities were detected in sera of mice treated with the agent at a dose of 100 mg/kg orally. Since viricidal and viristatic activities of the agent against influenza virus were not demonstrated, the antiviral effects of TJS-064 may be expressed through the host's antiviral functions including interferon production.     

The role of serpins in the surveillance of the secretory pathway

Serpins (serine protease inhibitors) constitute a class of proteins with an unusually wide spectrum of different functions at extracellular sites and within the nucleocytoplasmic compartment that extends from protease inhibition to hormone transport and regulation of chromatin organization. Recent investigations reveal a growing number of serpins acting in secretory pathway organelles, indicating that they are not simply cargo destined for export, but fulfill distinct roles within the classical organelle-coupled trafficking system. These findings imply that some serpins are part of a quality control system that monitors the export and possibly import routes of eukaryotic cells. The molecular targets of these serpins are often unknown, opening new avenues for future research.     

The role of symmetry in the interpretation of physical theories

The symmetries of a physical theory are often associated with two things: conservation laws (via e.g. Noether׳s and Schur׳s theorems) and representational redundancies (“gauge symmetry”). But how can a physical theory׳s symmetries give rise to interesting (in the sense of non-trivial) conservation laws, if symmetries are transformations that correspond to no genuine physical difference? In this paper, I argue for a disambiguation in the notion of symmetry. The central distinction is between what I call “analytic” and “synthetic“ symmetries, so called because of an analogy with analytic and synthetic propositions. “Analytic“ symmetries are the turning of idle wheels in a theory׳s formalism, and correspond to no physical change; “synthetic“ symmetries cover all the rest. I argue that analytic symmetries are distinguished because they act as fixed points or constraints in any interpretation of a theory, and as such are akin to Poincaré׳s conventions or Reichenbach׳s ‘axioms of co-ordination’, or ‘relativized constitutive a priori principles’.     

The role of probability arguments in the history of science

The paper examines Wesley Salmon’s claim that the primary role of plausibility arguments in the history of science is to impose constraints on the prior probability of hypotheses (in the language of Bayesian confirmation theory). A detailed look at Copernicanism and Darwinism and, more briefly, Rutherford’s discovery of the atomic nucleus reveals a further and arguably more important role of plausibility arguments. It resides in the consideration of likelihoods, which state how likely a given hypothesis makes a given piece of evidence. In each case the likelihoods raise the probability of one of the competing hypotheses and diminish the credibility of its rival, and this may happen either on the basis of ‘old’ or ‘new’ evidence.     

The role of the <Emphasis Type="Italic">trans</Emphasis>-Golgi network in varicella zoster virus biology

The task of assembling nascent virions presents a formidable challenge to large, enveloped DNA viruses such as varicella zoster virus (VZV). After parasitising the host cells compartmentalised biosynthetic machinery, viral constituents must be brought together in appropriate proportions for packaging and export. Recent evidence places the trans-Golgi network (TGN) in an orchestrating role with respect to the assembly, envelopment and egress of herpesviruses. This role accords with known functions of the TGN in the uninfected cell. The targeting of viral glycoproteins to the TGN appears to provide a crucial platform for viral assembly. Tegument proteins, interacting with the cytoplasmic domains of glycoproteins, in turn recruit nucleocapsids to the developing supramolecular array. Molecular studies are continually refining understanding of these processes, building upon elegant electron microscopic data. Knowledge of VZVs use of endogenous trafficking pathways from the TGN sheds light on important aspects of viral behaviour in vitro and in vivo.Received 22 June 2004; received after revision 22 August 2004; accepted 25 August 2004     

The role of meta-empirical theory assessment in the acceptance of atomism

The universal acceptance of atomism in physics and chemistry in the early 20th century went along with an altered view on the epistemic status of microphysical conjectures. Contrary to the prevalent understanding during the 19th century, on the new view unobservable objects could be ‘discovered’. It is argued in the present paper that this shift can be connected to the implicit integration of elements of meta-empirical theory assessment into the concept of theory confirmation.     

The role of time series analysis in the evaluation of econometric models

This paper compares the properties of a structural model—the London Business School model of the U.K. economy—with a time series model. Information provided by this type of comparison is a useful diagnostic tool for detecting types of model misspecification. This is a more meaningful way of proceeding rather than attempting to establish the superiority of one type of model over another. In lieu of a better structural model, the effects of inappropriate dynamic specification can be reduced by combining the forecasts of both the structural and time series models. For many variables considered here these provide more accurate forecasts than each of the model types alone.     

The role of phosphoenolpyruvate in insulin secretion: the effect of L-phenylalanine

Summary Incubation of rat islets with phenylalanine increased the tissue content of phosophoenolpyruvate, both in the presence and in the absence of glucose. At the same time, L-phenylalanine neither stimulated nor inhibited insulin release. It is unlikely that insulin secretion is tightly coupled to the availability of phosphoenolpyruvate in rat islets.